Field of the Invention:

The present invention relates to an improved process for the preparation of 2-[2-[3(S)-[3-[2-(7-Chloro-2-quniolinyI) ethenyl] phenyl]-3-hydroxypropyl] pheny]]-2-propanol, an intermediate utilized in the synthesis of Montelukast and its salts thereof

Background of the Invention:

Montelukast sodium namely Sodium l-[[[(lR)-l-[3-[(lE)-2-(7-chloro-2-quinolinyl) ethenyl] phenyl]-3-[2-(l-hydroxy-1-methylethyl) phenyl] propyl] thio] methyl] cyclo propane acetic acid has the formula

Montelukast sodium is a leukotriene antagonist and inhibits the synthesis of leukotriene biosynthesis. It is useful as anti-asthmatic, anti-allergic, anti-inflammatory, cytoprotective agent and hence useful in the treatment of angina, cerebral spasm, glomerular nephritis, hepatic, and toxemia, uveitis and allograft rejection.

EP 0,480,717 discloses Montelukast sodium along with other related compounds and the methods for their preparation. The reported method of synthesis proceeds through corresponding methyl ester namely, and involves coupling methyl l-(mercaptomethyl) cyclopropane acetate with a mesylate generated in-situ. The methyl ester is hydrolyzed to free acids and the latter converted directly to Montelukast sodium salt. The process is not suitable for large-scale production because it requires tedious chromatographic purification of the methyl ester intermediate and /or the final product with low yield.

Object of the Invention:

The main object of the present invention is to provide an improved process for the preparation of 2-[2-[3(S)-[3-[2-(7-Chloro-2-quniolinyl) ethenyl] phenyl]-3-hydroxypropyl] phenyl]-2-propanol.

Another object of the present invention is to provide a process for the preparation of Montelukast using2-[2-[3(S)-[3-[2-(7-Chloro-2-quniolinyl)ethenyi]phenyl]-3-hydroxypropyl]phenyl]-2- propanol prepared as per the present invention.

Summary of the Invention:

According to the main aspect of the present invention there is provided an improved process for the preparation of 2-[2-[3(S)-[3-[2-(7-Chloro-2-qunioIinyl) ethenyl] phenyl]-3-hydroxypropyl] phenyi]-2-propanol an intermediate for preparing Montelulcast, comprising the steps of; esterfication of anthranilic acid and treating obtained methyl anthranilate with Grignard reagent to afford 2-(2-aminophenyl) propan-2-ol; which upon diazotization yields 2-(2-iodophenyl) propan-2-ol. Obtained 2-(2-iodophenyl) propan-2-ol further condensed with l-(3-((E)-2-(7-chloroquinoIin-2-yl) vinyl) phenyl) prop-2-en-l-ol (vinyl intermediate), and simultaneously reduced to produce 2-[2-[3(S)-[3-[2-(7-Chloro-2-quniolinyl)ethenyl]phenyl]-3-hydroxypropyl] phenyl]-2-propanol (Monte-diol).

The entire reaction has been schematically represented over here.
Montelukast or its alkaline salts is further prepared from 2-[2-[3(S)-[3-[2-(7-Chloro-2-quniolinyl) ethenyl] phenyl]-3-hydroxypropyl] phenyl]-2-propanol by following the processes reported in the literature.

DETAILED DESCRIPTION OF THE INVENTION:

Therefore the present invention relates to an improved process for the preparation of 2-[2-[3(S)-[3-[2-(7-Chloro-2-quniolinyl) ethenyl] phenyl]-3-hydroxypropyl] phenyl]-2-propanol, which is an intermediate for preparing Montelukast and its further conversion to Montelukast or its sahs thereof

Accordingly the present invention provided a process for the preparation of 2-[2-[3(S)-[3-[2-(7-Chloro-2-quniolinyl)ethenyl]phenyl]-3-hydroxypropyl]phenyl]-2-propanol comprising the steps of,

• esterfication of anthranilic acid to attain methyl anthranilate
• treating methyl anthranilate with Grignard reagent to afford 2-(2-aminophenyl)propan-2-ol.
• diazotizing 2-(2-aminophenyl)propan-2-ol to yield 2-(2-iodophenyl)propan-2-ol.
• condensing 2-(2-iodophenyl)propan-2-ol with l-(3-((E)-2-(7-chloroquinolm-2-yl)vinyl) phenyl) prop-2-en-l-ol (vinyl intermediate) in presence of catalyst, base and solvent
• reducing the attained l-(3-((E)-2-(7-chloroquinolin-2-yl)vinyl)phenyl)-3-(2-(2-hydroxy propan-2-
yl)phenyl)propan-l-one in presence of reducing agent affords 2-[2-[3(S)-[3-[2-(7-Chloro-2-qunioIinyl) ethenyl] phenyl]-3-hydroxypropyi]phenyl]-2-propanol (Monte-diol).

According to the present invention esterification of anthranilic acid with dimethyl carbonate is carried out in presence of an acid affords methyl anthranilate, wherein the acid includes sulfuric acid or hydrochloric acid or HBF4.

Further, the above obtained methyl anthralinate reacts with Grignard reagent preferably methyl magnesium chloride in an organic solvent such as tetrahydrofuran provides 2-(2-aminophenyl) propan-2-ol.

Later 2-(2-aminophenyl) propan-2-ol on diazotization leads to diazonium salts; which further reacts with of Sodium or potassium Iodide produces 2-(2-iodophenyl) propan-2-ol.

According to the present invention, 2-(2-iodophenyl) propan-2-ol condensed with l-(3-((E)-2-(7-chloroquinolin-2-yl) vinyl) phenyl) prop-2-en-l-ol (vinyl intermediate) in the presence of a catalyst and a base produces l-(3-((E)-2-(7-chloroquinolin-2-yl)vinyl)phenyl)-3-(2-(2-hydroxypropan-2-yl)phenyl)propan-1 -one.

In one embodiment, the catalyst used in condensation reaction includes palladium acetate, LiOAc or LiCl;

In another embodiment, the base used in condensation reaction is selected from an alkyl amine preferably triethylamine.

In yet another embodiment the solvent used in condensation reaction is selected from acetonitrile, toluene or DMF.

According to the present invention l-(3-((E)-2-(7-chloroquinolin-2-yl)vinyl)phenyl)-3-(2-(2-ydroxypropan-2-yl)phenyl)propan-l-one selectively reduced in presence of suitable reducing agent   to   obtain 2-[2-[3(S)-[3-[2-(7-Chloro-2-quniolinyl)ethenyl]phenyl]-3-hydroxy propyl]phenyl]-2-propanol (Monte-diol).

In yet another embodiment, wherein the preferable reducing agent is (-)-Diisopinocampheyl chloroborane (DIP chloride).

As used herein, the term TEA refers to Triethylamine.

As used herein, the term DIP chloride refers to (-)-Diisopinocampheyl chloroborane
As used herein, the term DCM refers to dichloromethane.
Accordingly Montelukast or its pharmaceutically acceptable salts are further prepared from 2-[2-[3(S)-[3-[2-(7-Chloro-2-quniolinyl) ethenyl] phenyi]-3-hydroxypropyl]pheny}]-2-propanol (Monte-diol) by following various processes reported in the literature.

It is convenient to describe the invention herein in relation to particularly preferred embodiments relating to production of 2-[2-[3(S)-[3-[2-(7-Chloro-2-quniolinyl) ethenyl] phenyl]-3-hydroxypropyl] phenyl]-2-propanol. However, it is to be appreciated that other constructions and arrangements are also considered as falling within the scope of the invention. Various modifications, alterations, variations and or additions to the construction and arrangements described herein are also considered as falling within the ambit and scope of the present invention.

EXAMPLES:

The present invention will now be further explained in the following examples. However, the present invention should not be construed as limited thereby. One of ordinary skill in the art will understand how to vary the exemplified preparations to obtain the desired results.

Preparation of 2-f2-f3(S)-f3-[2-(7-Chloro-2-quniolinvnethenvllDhenvl1-3-hvdroxvpropvll phenvn-2-propanol:

Stage-1; Preparation of methyl anthranilate Dimethyl carbonate (224 ml) and of sulphuric acid (55 ml) were charged into a 1.0 It flask at 25-35°C. The temperature was raised to 65-70°C and anthralinic acid (100 g) was charged over 60 min in equal lots and in equal intervals at 65-70°C. Again the temperature was raised to 75-80°C and maintained for 24 hr at reflux temperature. The reaction completion was checked by TLC. After the reaction completion the reaction mass was cooled to 25-35°C and quenched into 8% NaHCOs solution (1000 ml) at a temperature of below 15°C. Reaction mass was stirred for 10 min and dichloromethane (1000 ml) was charged. pH was adjusted to 6.5-7.5 with 8% NaHCOs solution at 15-20°C. After that the temperature was raised to 25-35°C and stirred for 15 min. and settle for 30 min at 25-35°C. The organic layer was separated and the aqueous layer was again extracted with dichloromethane (200 ml). The organic layers were combined and washed twice with 20% NaCl solution (2x500ml) and evaporated completely at below 45°C under vacuum to get residue (weight 101 g).

Stage-2: Preparation of 2-(2-aminophenvn proDan-2-ol
Methyl anthranilate (100 g ) and Tetrahydrofuran (800 ml) were charged into a 3.0 It flask at 25-35°C under N2 atmosphere. The reaction mass was cooled to -5°C and methyl magnesium chloride (880 ml) was added slowly over 1-2 hr at -5 to 0°C. The reaction mass was maintained for 1 hr at 0-5°C u/Na. Reaction completion was checked by TLC and reaction mass was quenched into 12 % acetic acid (1000 ml) below 15°C. Reaction mass pH was adjusted to 6.5-7.5 with l:ldil acetic below 15°C. Reaction mass temperature was raised to 25-35°C and maintained for 30 min and settled for 30 min at 25-35°C. The organic layer was separated and the aqueous layer was extracted with ethyl acetate (400ml). The combined organic layer was washed with 8%NaHC03 (400ml) at 25-35°C and 5% NaCl solution (400ml). Organic layer was evaporated completely below 45°C under vacuum to get residue.

The above obtained residue was suspended in D.M.Water (500 ml) and pH was adjusted to 2.0 with 1:1 dil HCl at 25-30°C. Reaction mass was washed with toluene (500+250ml). Aqueous layer pH was adjusted to 6.0-7.0 with aq.ammonia at 25-30°C. Reaction mass was extracted with dichloromethane (500+250ml) and washed with the combined organic layer with DM water (2x250ml). The separated organic layer was evaporated completely below 40°C under vacuum to get residue (weight 90g).

Stage-3; Preparation of 2-f2-iodophenvn propan-2-ol.
D.M.Water (640ml) and CP HCl (140ml) were charged into 3.0 It flask and cooled to 0°C. 2-(2-aminophenyl) propan-2-ol (100 g) was charged at 0-5 °C to the above solution and stirred for 15 min. To the reaction mass chilled sodium nitrite solution (46 g of NaN02 dissolve in 165ml of D.M. Water) was added slowly over 30 min at 0 to 5°C and maintained for 30 min at 0 to 5°C. Potassium iodide (171.3 g of KI dissolve in 360 ml of 1 M HCl) was added to the reaction mass over 30 min at 0 to 5°C. Reaction mass temperature was raised to 20-25°C and maintain for 60 min at 20-25°C. Reaction completion was monitored by TLC. Reaction mass was cooled to 10°C and 8% NaHCOs solution (1000 ml) was added and pH was adjusted to 6.5-7.5 with 8% NaHCOs below 15°C. Reaction mass was extracted with ethyl acetate (500+500ml). The combined organic layer was washed with 50% sodium thiosulphate solution (400ml) and 25% NaCl solution (1000 ml) at 25 to 35°C. The separated organic layer was evaporated completely below 50°C under vacuum to get residue. And the obtained crude material was purified by column chromatography (weight 85g).

Stage-4; Preparation of l-(3-((EV2-(7-chloroQuinolm-2-vn vinvlVphenvlV3-(2-(2-hydroxvpropan-2-vn phenyl) propan-1-one l-(3-((E)-2-(7-Chloroquinolin-2-yl)phenyI)prop-2-en-l-ol (lOOg), 2-(2-iodophenyl) propan-2-ol (85.5g) and acetonitrile (300ml) were charged at 25-35°C. Palladium (II) acetate (0.7g) and triethylamine (88.6ml) were charged at 25-35°C u/Ni atmosphere. The reaction mass temperature was raised to reflux (78-82°C) under N2 atmosphere and maintained there for 10-20 hr till the reaction was completed. The reaction mixture was cooled to 55°C and acetonitrile (200ml) was added. Again temperature was raised to 65°C and maintained for Ihr. The reaction mass was filtered and washed with acetonitrile (100ml). Solvent was completely distilled out u/vacuum to get the residue. Methanol (500ml) was added to the residue and stirred for 30 min. 10% methanolic HCl (100ml) was added and stirred for 1 hr at 25-30°C. The reaction mass was filtered and washed with methanol (100ml). The wet product was allowed to dry for 2hr at 25-35°C. Dichloromethane (500ml) was charged to the dried material and stirred for 10 min to which D.M.Water (300ml) was charged. The reaction mass pH was adjusted to 6.0-7.0 with aq.ammonia at 25-30°C and the phases were allowed to separate. The aqueous layer was extracted with dichloromethane and total organic layer was washed with D.M.Water (500ml). The organic layer was evaporated to dryness and the methanol (500ml) was added to the semisolid. The mixture was heated to reflux for Ihr and then cooled to 25-35°C. The solid was filtered off, washed with methanol (50ml) and dried at 50-55°C for 6 hr to give the title compound (weight 62g)

Stage-5; Preparation of 2-f2-f3(S)-f3-f2-(7-Chloro-2-Quniolinvnethenvl1 phenvll-S-hvdroxypropyll phenyl]-2-propanol
Dichloromethane (600ml) was charged and cooled to 10-12°C u/N2atmosphere to which Dip chloride (240ml) was added. The reaction mixture was cooled to -5 to 0°C U/N2 atmosphere. Stage-4 solution was added at -5 to 0°C over 4-6 hr (100 g of stage-4 dissolved in 1000 ml of dichloromethane) and maintained for 12 hrs at -5 to 0°C under N2 atmosphere. After the reaction was completed, Acetone (60ml) was added at -5 to 5°C slowly over 30-60min and stirred for 45 min at 0-5°C. This reaction mixture was added to diethanol amine (135g mixed with 1750 ml DM water) at 20-25°C over 30 min. Dichloromethane (600ml) was added and then maintained for 3 hrs at 20-25 °C and allowed to separate the layers. The aqueous layer was extracted with dichloromethane (600ml). The combined organic layer was washed with of 5% NaCl (1000ml) and solvent was distilled out completely with vacuum at temperature below 40°C to get the residue, to which n-hexane (500ml) was added at 25-35°C, stirred for Ihr and n-hexane was decanted. Traces of n-hexane were removed by degassing the residual mass 1 hr at < 40°C and cooled to 25-35°C. Toluene (50ml) was charged, stirred for 30 min. Isopropyl ether (250ml) was added slowly over 1 hr at 25-35°C and maintained for 4 hr. The mass was filtered off, washed the wet cake with isopropyl ether (50ml) and dried at 40-45°C for 8 hr to obtain the title compound (weight 60 g)

We claim:

1. An improved process for the preparation of 2-[2-[3(S)-[3-[2-(7-Chloro-2-quniolinyl) ethenyl] phenyl]-3-hydroxypropyl] phenyl]-2-propanol comprising the steps of,

a) esterfication of anthranilic acid to attain Methyl anthranilate
b) treating Methyl anthranilate with a Grignard reagent to afford 2-(2-aminophenyl) propan-2-ol.
c) diazotizing 2-(2-aminophenyl) propan-2-ol to yield 2-(2-iodophenyl) propan-2-ol.
d) condensing 2-(2-iodophenyl) propan-2-ol with l-(3-((E)-2-(7-chloroquinolin-2-yl) vinyl) phenyl) prop-2-en-l-ol (vinyl intermediate) in presence of a catalyst.
e) Reducing the attained l-(3-((E)-2-(7-chloroquinolin-2-yl)vinyl)phenyl)-3-(2-(2-hydroxy propan-2-yl)phenyl)propan-l-one in presence of reducing agent to afford 2-[2-[3(S)-[3-[2-(7-Chloro-2-quniolinyl)ethenyl]phenyl]-3-hydroxypropyl] phenyl] -2-propanol (Monte-diol).
f) Converting 2-[2-[3(S)-[3-[2-(7-Chloro-2-quniolinyl) ethenyl]phenyl]-3-hydroxy propyl]phenyl]-2-propanol (Monte-diol) to Montelukast or its pharmaceutically acceptable salts.

2. The process according to claim 1, wherein esterification in step (a) is carried out in presence of dimethyl carbonate and an acid;

3. The process according to claim 1, wherein esterification in step (a) wherein acid includes sulfuric acid or hydrochloric acid or HBF4.

4. The process according to claim 1, wherein diazotization in step (c) leads to diazonium salts which further reacts with Sodium or Potassium Iodide produces 2-(2-iodophenyl) propan-2-ol.

5. The process according to claim 1, wherein catalyst used in condensation reaction in step (d) includes palladium acetate, LiOAc, or LiCl.

6. The process according to claim 1, wherein base used in step (d) is preferably an alkylamine.

7. The process according to claim 1, wherein the solvent used in step (d) includes acetonitrile, toluene or DMF. .

8. The process according to claim 1, wherein selective reduction in step (e) is carried out m presence of reducing agent such as (-)-Diisopinocampheyl chloroborane (DIP chloride).

9. Use of 2-[2-[3(S)-[3-[2-(7-Chloro-2-quniolinyl) ethenyl] phenyl]-3-hydroxypropyl] phenyl]-2-propanol (Monte-diol) for the preparation of Montelukast or its salts thereof